Immune thrombocytopenia (ITP) is an autoimmune bleeding disease due to decreased platelet production as well as accelerated platelet destruction mediated in part by autoantibody-based destruction mechanisms. We and others have identified a dysregulated immune response in ITP patients as evidenced by impaired regulatory T and B cells which may be responsible for this activated autoimmune state. There is a tight relationship between innate and adaptive immune responses and our data indicate that monocyte subsets, which can influence T cell responses, are altered in their ability to polarize T cell responses in ITP patients, suppressing Treg expansion while promoting Th1 development. Furthermore, in ITP patients who are treated with megakaryocytic stimulating thrombopoietic (TPO) agents only responders to treatment have normalized monocyte and Treg compartments. In addition, we have discovered that platelets from chronic ITP patients with low platelet counts express high levels of proinflammatory molecules and those platelet-derived factors in ITP patients alter dendritic cell (DC) maturation such that they in turn inhibit Treg proliferation. We hypothesize that aberrant interactions between T cells and innate immune cells due to increased platelet reactivity in ITP patients are responsible for altered Treg/Th development in ITP patients and that responsiveness to TPO agents is dependent on normalization of these interactions. We will test our hypothesis with the following specific aims: 1) to dissect mechanisms of altered DC-Treg interactions in patients with ITP, 2) to characterize the role of platelets in skewed Treg/Th responses in ITP patients, and 3) to identify the relationship between platelet reactivity and control of Treg/Th responses by DCs during treatment with TPO agents. We believe that the proposed studies will provide mechanistic explanations for the ways in which innate immune abnormalities can contribute to pathogenic autoimmunity in ITP and modulate response or non-responsive to TPO agents and possibly other ITP therapies.